Plasma turnover of HDL apoC-I, apoC-III, and apoE in humans

Abstract

Numerous factors are known to affect the plasma metabolism of HDL, including lipoprotein receptors, lipid transfer protein, lipolytic enzymes and HDL apolipoproteins. In order to better define the role of HDL apolipoproteins in determining plasma HDL concentrations, the aims of the present study were: a ) to compare the in vivo rate of plasma turnover of HDL apolipoproteins [i.e., apolipoprotein A-I (apoA-I), apoC-I, apoC-III, and apoE], and b ) to investigate to what extent these metabolic parameters are related to plasma HDL levels. We thus studied 16 individuals with HDL cholesterol levels ranging from 0.56-1.66 mmol/l and HDL apoA-I levels ranging from 89-149 mg/dl. Plasma kinetics of HDL apolipoproteins were investigated using a primed constant (12 h) infusion of deuterated leucine. Plasma HDL apolipoprotein levels were 41.8 ؎ 1.5, 9.7 ؎ 0.5, 4.9 ؎ 0.5, and 0.7 ؎ 0.1 mol/l for apoA-I, apoC-I, apoC-III and apoE. Plasma transport rates (TRs) were 388.6 ؎ 24.7, 131.5 ؎ 12.5, 66.5 ؎ 9.1, and 31.4 ؎ 3.3 nmol·kg ؊ 1 ·day ؊ 1 ; and residence times (RTs) were 5.1 ؎ 0.4, 3.7 ؎ 0.3, 3.6 ؎ 0.3, and 1.1 ؎ 0.1 days, respectively. HDL cholesterol and apoA-I levels were significantly correlated with HDL apoA-I RT ( r ‫؍‬ 0.69 and r ‫؍‬ 0.56), and were not significantly correlated with HDL apoA-I TR. In contrast, HDL apoC-I, apoC-III, and apoB levels were all positively related to their TRs and not their RTs. HDL apoC-III TR was postively correlated with levels of HDL apoC-III ( r ‫؍‬ 0.73, P Ͻ 0.01), and with those of HDL cholesterol and apoA-I ( r ‫؍‬ 0.54 and r ‫؍‬ 0.53, P Ͻ 0.05, respectively). HDL apoC-III TR was in turn related to HDL apoA-I RT ( r ‫؍‬ 0.51, P Ͻ 0.05). Together, these results provide in vivo evidence for a link between the metabolism of HDL apoC-III and apoA-I, and suggest a role for apoC-III in the regulation of plasma HDL levels. Low plasma levels of HDL are associated with increased risk of coronary heart disease (CHD) (1, 2). A strong therapeutic rationale therefore exists for increasing plasma HDL levels of patients at risk for CHD. An ongoing search for novel therapeutic agents able to increase plasma HDL levels (3) depends on a clear understanding of the many metabolic factors that affect plasma HDL metabolism. These include a ) lipoprotein receptors, e.g., scavenger receptor class B type I (SR-BI) and the adenosine triphosphate binding cassette transporter (ABCA1) (4, 5); b ) lipid transfer proteins, e.g., cholesteryl ester transfer protein and phospholipid transfer protein (6); c ) lipolytic enzymes, e.g., lipoprotein lipase, hepatic lipase (HL), and endothelial lipase (7); and d ) HDL apolipoproteins, e.g., apolipoprotein A-I (apoA-I) and apoA-II (8).Many studies have investigated the physiological role of apolipoproteins that readily exchange between plasma lipoproteins (i.e., apoC-I, apoC-III, and apoE). The majority of this work has focused on the effect of these proteins on triglyceride-rich lipoprotein (TRL) metabolism; however, there is ample evidence that these proteins can ...

Sitagliptin Results in a Decrease of Truncated Apolipoprotein C1

“…The decline of truncated protein was consistent with the target level for DPP-4 inhibition by sitagliptin. Given a mean residence time for ApoC1 of 3.7 + 0.3 days [ 28 ], or a half-life of 2.56 days, full inhibition of DPP-4 should result in a 50% decline of truncated protein in approximately 2.56 days. Assuming first-order kinetics with respect to ApoC1 and DPP-4, fifty percent decline in 3.0 days corresponded to approximately 85% inhibition of DPP-4, very nearly the target for drug administration [ 29 ].…”

A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels

“…Dyslipidemia, metabolic syndrome, insulin resistance, visceral adiposity, chronic renal insufficiency, and several other systemic metabolic diseases are associated with elevated apoC-III levels, which may be due to both increased apoC-III production and apoC-III secretion on VLDL 15–18 , as well as to delayed TRL clearance 11–14 . ApoC-III exchanges rapidly among TRLs, lipoprotein remnants, and HDLs in humans 19,20 , which has made accurate assessment of the kinetics and metabolism of apoC-III in humans challenging 14,21,22 . Some studies have identified apoC-III on LDLs as a marker of a small, dense proath-erogenic phenotype for LDL 23,24 .…”

Lipoprotein Subclass Profile after Progressive Energy Deficits Induced by Calorie Restriction or Exercise

“…Our findings indicate that EX did not affect HDL-cholesterol concentration ( p = 0.913). HDL turns over rather slow (half-life in the order of several days) [ 37 ], hence it is rather unlikely for any effects to manifest acutely, even though some studies have reported acute changes after exercise [ 38 , 39 ]. Chronic aerobic exercise training, however, can bring about a modest increase in HDL-cholesterol concentration [ 40 ].…”